The present invention relates to the fields of benzoxazines, benzothiazines, and related compounds and to their medical use.
Nitric oxide (NO) has diverse roles both in normal and pathological processes, including the regulation of blood pressure, in neurotransmission, and in the macrophage defense systems (Snyder, S. H. and Bredt, D. S., Scientific American, May; 266(5) 1992: 68). NO is synthesized by three isoforms of nitric oxide synthase, a constitutive form in endothelial cells (eNOS), a constitutive form in neuronal cells (nNOS), and an inducible form found in macrophage cells (iNOS). These enzymes are homodimeric proteins that catalyze a five-electron oxidation of L-arginine, yielding NO and citrulline. The role of NO produced by each of the NOS isoforms is quite unique. Overstimulation or overproduction of individual NOS isoforms, especially nNOS and iNOS, plays a role in several disorders, including septic shock, arthritis (Boughton-Smith et al., IDrugs 1:321-334, 1998 and Cochrane et al., Med. Res. Rev. 16: 547-563, 1996), diabetes, ischemia-reperfusion injury, pain (Larson et al., Pain 86:103-111, 2000), and various neurodegenerative diseases (Kerwin et al., J. Med. Chem. 38:4343, 1995), while eNOS inhibition leads to unwanted effects such as enhanced white cell and platelet activation, hypertension, and increased atherogenesis (Valance et al., Nature Rev. Drug Disc. 1:939, 2002).
NOS inhibitors have the potential to be used as therapeutic agents in many disorders. However, the preservation of physiologically important nitric oxide synthase function suggests the desirability of the development of isoform-selective inhibitors that preferentially inhibit nNOS, or nNOS and iNOS, over eNOS. Specifically, selective NOS inhibitors, particularly for nNOS or iNOS, are candidates for use in the treatment of chronic pain states such as neuropathic pain, chronic tension type headache or transformed migraine wherein the pain state results from the persistence of peripheral and/or central sensitization.